Cellular Pathway Could Be Used To Reprogram the Body’s Immune System

IMB researchers have identified a pathway in cells that could be used to reprogram the body’s immune system to fight back against both chronic inflammatory and infectious diseases.

Targetting both bacteria and inflammation

Dr Kaustav Das Gupta and Professor Matt Sweet from IMB discovered that a molecule derived from glucose in immune cells can both stop bacteria growing and dampen inflammatory responses.

Dr Das Gupta said the finding is a critical step towards future therapeutics that train immune cells.

Reprogramming the immune system

“The effects of this molecule called ribulose-5-phosphate on bacteria are striking – it can cooperate with other immune factors to stop disease-causing strains of the E. coli bacteria from growing,” Dr Das Gupta said.

“It also reprograms the immune system to switch off destructive inflammation, which contributes to both life-threatening infectious diseases such as sepsis as well as chronic inflammatory diseases like respiratory diseases, chronic liver disease, inflammatory bowel disease, rheumatoid arthritis, heart disease, stroke, diabetes and dementia.”

The research was carried out on a strain of E. coli bacteria that causes approximately 80 per cent of urinary tract infections and is a common cause of sepsis.

Preclinical trials were used to confirm the role of this pathway in controlling bacterial infections.

Professor Sweet said human cells were also used to demonstrate that ribulose-5-phosphate reduces the production of molecules that drive chronic inflammatory diseases.

Boosting the immune pathway

“Host-directed therapies which train our immune systems to fight infections, will become increasingly important as more types of bacteria become resistant to known antibiotics,” Professor Sweet said.

“A bonus is that this strategy also switches off destructive inflammation, which gives it the potential to combat chronic disease.

“By boosting the immune pathway that generates ribulose-5-phosphate, we may be able to give the body the power to fight back against inflammatory and infectious diseases – not one, but two of the major global challenges for human health.”

New therapies on the horizon

Many current anti-inflammatory therapies target proteins on the outside of cells but because this pathway occurs inside cells, the researchers devised a new approach to target the pathway using mRNA technology.

Professor Sweet said the technology has shown promising results to deliver the enzyme that generates ribulose-5-phosphate into immune cells and has been filed as a provisional patent by UniQuest, UQ’s commercialisation company.

The work involved international and national cooperation, including IMB researchers Professor David Fairlie and Professor Mark Schembri as key collaborators.

Reference: Das Gupta K, Ramnath D, von Pein JB, et al. HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages. PNAS. 2023;120(4):e2212813120. doi: 10.1073/pnas.2212813120

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